Antifungal Drugs

Abstract

We reviewed the licensed antifungal drugs and summarized their mechanisms of action, pharmacological profiles, and susceptibility to specific fungi. Approved antimycotics inhibit 1,3-β-d-glucan synthase, lanosterol 14-α-demethylase, protein, and deoxyribonucleic acid biosynthesis, or sequestrate ergosterol. Their most severe side effects are hepatotoxicity, nephrotoxicity, and myelotoxicity. Whereas triazoles exhibit the most significant drug-drug interactions, echinocandins exhibit almost none. The antifungal resistance may be developed across most pathogens and includes drug target overexpression, efflux pump activation, and amino acid substitution. The experimental antifungal drugs in clinical trials are also reviewed. Siderophores in the Trojan horse approach or the application of siderophore biosynthesis enzyme inhibitors represent the most promising emerging antifungal therapies.

Keywords: amphotericin B; antifungal drugs; echinocandins; flucytosine; invasive fungal infections; resistance; siderophores; triazoles.

Figure 1

Sixty-five years of antifungal therapy. Most antifungal agents were discovered in the most recent three decades. Colored dots refer to specific antifungal drug class—polyenes (blue), pyrimidine analogues (purple), triazoles (green), and echinocandins (orange). Antifungal drugs under development and/or testing in clinical trials are marked black (see the chapter Antifungal pipeline for further information). AMB = amphotericin B, 5-FC = flucytosine, FLC = fluconazole, ITC = itraconazole, CSF = caspofungin, VOR = voriconazole, MCF = micafungin, POS = posaconazole, ANF = anidulafungin, ISV = isavuconazole, SUBA-ITC = super bioavailable itraconazole.

Figure 2

Chemical structures of the licensed antifungal drugs: amphotericin B (A); flucytosine (B), and its deaminated product 5-fluorouracil (C); fluconazole (D); itraconazole (E); voriconazole (F); posaconazole (G); and isavuconazole (H). The substructures necessary for biological activity are in blue.

Figure 3

Mechanisms of actions of antifungals in the fungal cell. (A): In the fungal cytoplasm, AMB induces ROS formation resulting in the mitochondrial, biomembrane, DNA, and protein damage. Furthermore, 5-FC prevents DNA, RNA, and thus protein biosynthesis. (B): In the fungal biomembrane, 1,3-β-d-glucan synthase (1) and 14-α-demethylase (2) are inhibited by echinocandins and triazoles, respectively. Additionally, ergosterol contained in the biomembrane is sequestered by AMB, resulting in pore formation.

Figure 4

Echinocandins caspofungin (A), micafungin (B), and anidulafungin (C). The homotyrosine amino acid residue (blue) is mandatory for the inhibition of the 1,3-β-d-glucan synthase catalytic subunit Fks. The amino acid core (black) contributes to the antifungal potency and determines the physicochemical properties. Moreover, ethylenediamine, sulphate and hydroxyl groups (pink) contribute to water solubility. Specific lipophilic side chains (orange) decrease the hemolytic activity.

Figure 5

Metabolites of micafungin. Top: The original sulphate group (blue) on the dihydroxyhomotyrosine amino acid residue is metabolized to a hydroxyl group followed by its methylation. Bottom: the third and minor metabolite arises from hydroxylation of the methyl group (orange) at the ω₁ position of the lipophilic side chain. COMT = catechol-O-methyltransferase.

Figure 6

The emergence of microbial resistance is given by three main factors, including choice of antifungal treatment, type of fungal species, and patient medical history. For example, adequate dosing and distinguishing between fungistatic/fungicidal drug effects are mandatory for successful treatment. Unfortunately, repeated antifungal therapy and often prophylaxis narrow the appropriate drug selection. With the fungal biofilm formation, this task becomes more problematic. Furthermore, fungi often decrease drug concentration by efflux pump activation or target overexpression. Additionally, these targets can be amplified or changed due to several types of mutations, such as amino acid substitution. Modified from [64,65].

Figure 7

Future antifungal therapy may benefit from these substances including tetrazoles VT-1129 (A), VT-1161 (B), VT-1598 (C); triazole PC1244 (D); echinocandin rezafungin (E); triterpenoid Ibrexafungerp (F); inositol transferase inhibitor Fosmanogepix (G); dihydroorotate dehydrogenase inhibitor Olorofim (H); histone deacetylase inhibitor MGCD290 (I); monoterpenoids citronellal (J) and perillaldehyde (K); brominated acylhydrazones BHBM (L) and its derivative D13 (M); triterpenoid celastrol (N); and hydroxamate type siderophore VL-2397 (O).